Melanoma

Overview

Definition

Melanoma is a malignant tumor Tumor Inflammation arising from melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions, the melanin-producing cells of the epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions.

Epidemiology

• 5th most common malignancy Malignancy Hemothorax in men and women in the United States
• Average age at diagnosis: 57 years
• Increasing incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency worldwide:
  • In Queensland, Australia (highest): 72 per 100,000
  • In the United States: 27 per 100,000
• The deadliest skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions cancer

Etiology

• Excessive exposure to ultraviolet A (UVA) and B (UVB) radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma:
  • Exposure to sunlight (UVB more closely associated with melanoma)
  • Highest in equatorial areas (when adjusted for skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions type), where UVB is more intense
  • Use of tanning beds (UVA)
  • ↑ number of blistering sunburns = ↑ risk
  • Exposure to psoralen and UVA radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma as treatment for psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis or other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions conditions
• Role of sunscreen:
  • Sunscreen users likely to have more sun exposure than the general public
  • Sunscreen protective mostly against UVB (increasing risk for UVA exposure)
• Genetic predisposition and personal characteristics:
  • Positive family history Family History Adult Health Maintenance in 5%–10% of cases
  • Fair skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, blue eyes, fair/red hair, freckles Freckles Primary Skin Lesions
  • Presence of > 40 melanocytic nevi Melanocytic Nevi Nevus/Nevi (a marker for ↑ risk)
  • Genetic syndromes:
    • Familial atypical multiple mole Mole Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi melanoma ( FAMMM FAMMM Clinically atypical nevi (usually exceeding 5 mm in diameter and having variable pigmentation and ill defined borders) with an increased risk for development of non-familial cutaneous malignant melanoma. Biopsies show melanocytic dysplasia. Nevi are clinically and histologically identical to the precursor lesions for melanoma in the B-K mole syndrome. Exocrine Pancreatic Cancer) syndrome: an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance genetic condition characterized by the presence of multiple atypical moles Moles Primary Skin Lesions
    • Xeroderma pigmentosum Xeroderma pigmentosum A rare, pigmentary, and atrophic autosomal recessive disease. It is manifested as an extreme photosensitivity to ultraviolet rays as the result of a deficiency in the enzyme that permits excisional repair of ultraviolet-damaged DNA. Lentigo Maligna: an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance condition caused by a defect in DNA repair mechanisms DNA repair mechanisms Although DNA fidelity is highly protected, DNA can still be damaged by a number of environmental factors, reactive oxygen species, and errors in DNA replication. DNA repair is a continuous process in which the cell corrects the damage. The cell has multiple mechanisms it can use to repair DNA. DNA Repair Mechanisms that leads to ultraviolet light Ultraviolet light That portion of the electromagnetic spectrum immediately below the visible range and extending into the x-ray frequencies. The longer wavelengths (near-uv or biotic or vital rays) are necessary for the endogenous synthesis of vitamin D and are also called antirachitic rays; the shorter, ionizing wavelengths (far-uv or abiotic or extravital rays) are viricidal, bactericidal, mutagenic, and carcinogenic and are used as disinfectants. Bullous Pemphigoid and Pemphigus Vulgaris sensitivity (i.e., severe sunburns) and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions cancer development 
• Immunosuppression:
  • Transplant patients Transplant patients Individuals receiving tissues or organs transferred from another individual of the same or different species, or from within the same individual. Human Herpesvirus 8
  • Hematologic malignancies

Anatomy

• Melanomas most commonly arise from the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions.
• Mucosal surfaces: about 1% of cases
  • Head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess region: oral, nasal, and paranasal cavities
  • Anorectal region
  • Vulvovaginal region
• Eyes:
  • Uvea Uvea The pigmented vascular coat of the eyeball, consisting of the choroid; ciliary body; and iris, which are continuous with each other. Eye: Anatomy (95% of ocular melanomas)
  • Conjunctiva Conjunctiva The mucous membrane that covers the posterior surface of the eyelids and the anterior pericorneal surface of the eyeball. Eye: Anatomy

Pathophysiology and Classification

Pathogenesis

• Most melanomas arise in epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions as slow-growing indolent tumors.
• May arise in preexisting precursor lesion/ nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi or de novo (from healthy skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions).
• Types of nevi Nevi Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi considered precursors to melanoma:
  • Common acquired nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
  • Dysplastic nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
  • Congenital Congenital Chorioretinitis nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
  • Cellular blue nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi
• Commonly found mutations:
  • CDKN2A (most common specific mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in familial melanoma)
  • BRAF (most common in superficial spreading melanoma)
  • KIT (most common in lentigo maligna Lentigo Maligna Lentigo maligna is melanoma in situ, a precancerous lesion that may progress to an invasive melanoma (specifically lentigo maligna melanoma subtype). This condition typically occurs in sun-damaged areas (e.g., face and neck) of elderly patients. Lentigo Maligna melanoma and acral–lentiginous melanoma)
  • RAS RAS Renal artery stenosis (RAS) is the narrowing of one or both renal arteries, usually caused by atherosclerotic disease or by fibromuscular dysplasia. If the stenosis is severe enough, the stenosis causes decreased renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS) and leads to renovascular hypertension (RVH). Renal Artery Stenosis
  • NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1
• Phases of growth:
  • Horizontal growth (radial growth):
    • Along the dermal–epidermal junction Dermal–Epidermal Junction Bullous Pemphigoid and Pemphigus Vulgaris
    • Most melanomas at this stage do not metastasize.
    • Microinvasion into the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions may be present at this stage.
  • Vertical growth:
    • Clearly invasive deep into the dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions
    • Associated with metastatic potential

Morphologic types

Major types:

Uncommon variants:

• Amelanotic melanoma:
  • Consists of poorly differentiated/dedifferentiated melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions
  • Present with lightly colored (pink/red) flat or raised lesions
  • Confused with benign Benign Fibroadenoma lesions (e.g., melanocytic nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi), leading to delay in diagnosis (worse prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas)
• Spitzoid melanoma:
  • Resembles Spitz tumors
  • Growing lesions: papules/nodules that may present with red, brown, black, or blue color
• Desmoplastic melanoma: rare, slow-growing, pale plaques or nodules resembling a scar Scar Dermatologic Examination
• Pigment-synthesizing melanoma (melanocytoma): 
  • Indolent type of blue-black nodules
  • Low risk of metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis

Classification

Breslow depth:

• A standardized method of melanoma depth measurement 
• Use of an optical micrometer fitted to the microscope to measure from the top of the epidermal granular layer to the deepest tumor Tumor Inflammation invasion
• Utilized in the 8th edition of the American Joint Committee on Cancer tumor Tumor Inflammation staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis system (but tumor Tumor Inflammation thickness recorded to the nearest 0.1 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma instead of the original 0.01 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma)

Clinical Presentation

Cutaneous melanomas (most common)

• Majority present with new skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion (de novo):
  • Suspicious pigmented lesion
  • Pruritus Pruritus An intense itching sensation that produces the urge to rub or scratch the skin to obtain relief. Atopic Dermatitis (Eczema) or bleeding may be present. 
• A preexisting nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi:
  •  Change in shape, size, or color
  • “Ugly duckling” sign: 1 different-looking mole Mole Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi among other moles Moles Primary Skin Lesions that are predominantly of similar morphology

Other melanomas

• Subungual:
  • Brown or black nail band
  • With or without nail dystrophy
  • Extension Extension Examination of the Upper Limbs of the pigment onto the nailfold 
  • Most commonly affects great toe and thumb
• Ocular:
  • Can be asymptomatic
  • Change in pupil Pupil The pupil is the space within the eye that permits light to project onto the retina. Anatomically located in front of the lens, the pupil’s size is controlled by the surrounding iris. The pupil provides insight into the function of the central and autonomic nervous systems. Pupil: Physiology and Abnormalities shape
  • Pigmented spot on the iris
  • Vision Vision Ophthalmic Exam changes
• Anal: signs and symptoms similar to other anal cancers

Diagnosis

History

• Sun exposure (occupational or recreational)
• Family history Family History Adult Health Maintenance
• History of previous melanomas

Physical exam

• Regular Regular Insulin skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions exam: should be thorough and comprehensive (entire body) and done under optimal lighting
• Adjunctive techniques:
  • Dermoscopy Dermoscopy A noninvasive technique that enables direct microscopic examination of the surface and architecture of the skin. Seborrheic Keratosis
  • Reflectance confocal microscopy (allows visualization of cells of epidermis Epidermis The external, nonvascular layer of the skin. It is made up, from within outward, of five layers of epithelium: (1) basal layer (stratum basale epidermidis); (2) spinous layer (stratum spinosum epidermidis); (3) granular layer (stratum granulosum epidermidis); (4) clear layer (stratum lucidum epidermidis); and (5) horny layer (stratum corneum epidermidis). Skin: Structure and Functions and papillary dermis Dermis A layer of vascularized connective tissue underneath the epidermis. The surface of the dermis contains innervated papillae. Embedded in or beneath the dermis are sweat glands; hair follicles; and sebaceous glands. Skin: Structure and Functions)
  • Computer-assisted diagnosis
• ABCDE criteria ABCDE criteria Nevus/Nevi: 
  • Developed to differentiate benign Benign Fibroadenoma melanocytic lesions from melanomas 
  • Further evaluation is warranted if the lesion meets ≥ 1 of the following criteria:
    • A ( asymmetry Asymmetry Examination of the Upper Limbs): asymmetrical shape
    • B (border): irregular/indistinct border
    • C (color): varying pigmentation or irregularly distributed
    • D (diameter): > 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
    • E (evolution): change in size, shape, or color; exceptional nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi different from other nevi Nevi Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi

Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma

• Excisional full-thickness biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma (gold standard):
  • Complete excision of lesion with 1 to 3 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma margin of normal skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions
  • Histopathologic diagnosis based on a combination of features, including:
    • Atypical melanocytes Melanocytes Mammalian pigment cells that produce melanins, pigments found mainly in the epidermis, but also in the eyes and the hair, by a process called melanogenesis. Coloration can be altered by the number of melanocytes or the amount of pigment produced and stored in the organelles called melanosomes. The large non-mammalian melanin-containing cells are called melanophores. Skin: Structure and Functions with large nuclei, prominent nucleoli
    • Architectural asymmetry Asymmetry Examination of the Upper Limbs
    • Poor circumscription (cells at the edge noted to be single, small instead of nested)
    • Lower epidermal and dermal cells vary in size and shape.
  • Immunohistochemistry Immunohistochemistry Histochemical localization of immunoreactive substances using labeled antibodies as reagents. Myeloperoxidase Deficiency (e.g., S-100, Sox10 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis expressed by almost all melanomas)
  • Gives information about the Breslow stage and ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers status (both needed for staging Staging Methods which attempt to express in replicable terms the extent of the neoplasm in the patient. Grading, Staging, and Metastasis and prognostic assessment)
• Incisional biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma:
  • For large lesions
  • If lesion is in difficult or cosmetically sensitive area (e.g., facial, subungual)

Adjunctive studies

Adjunctive studies are used for evaluation of metastatic disease.

• Laboratory studies:
  • CBC
  • Liver function tests Liver function tests Liver function tests, also known as hepatic function panels, are one of the most commonly performed screening blood tests. Such tests are also used to detect, evaluate, and monitor acute and chronic liver diseases. Liver Function Tests
  • LDH LDH Osteosarcoma
• Imaging:
  • Chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests: for lung metastases
  • Ultrasound: for lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
  • CT or PET PET An imaging technique that combines a positron-emission tomography (PET) scanner and a ct X ray scanner. This establishes a precise anatomic localization in the same session. Nuclear Imaging: for distant metastases

Staging

Management and Prognosis

Surgery

Wide local excision:

• Mainstay of treatment
• The recommended margins depend on lesion thickness.
• Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions graft Graft A piece of living tissue that is surgically transplanted Organ Transplantation may be required for closure depending on size and location.
• For acral/ subungual melanoma, digital amputation Amputation An amputation is the separation of a portion of the limb or the entire limb from the body, along with the bone. Amputations are generally indicated for conditions that compromise the viability of the limb or promote the spread of a local process that could manifest systemically. Amputation may be required.

Mohs micrographic surgery:

• Specialized technique in removal of locally invasive skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions cancers
• Controversial in melanoma (as there are no clinical trials comparing it to wide local excision)
• Used for in situ melanoma and lentigo maligna Lentigo Maligna Lentigo maligna is melanoma in situ, a precancerous lesion that may progress to an invasive melanoma (specifically lentigo maligna melanoma subtype). This condition typically occurs in sun-damaged areas (e.g., face and neck) of elderly patients. Lentigo Maligna of the head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess
• Not for invasive melanoma

Additional procedures

Sentinel lymph node biopsy Lymph Node Biopsy Lymphadenopathy (SLNB):

• Sentinel lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node (SLN): first draining lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node in the lymphatic system Lymphatic system A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs of the tumor Tumor Inflammation
• Performed for clinically negative nodes (to detect occult metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis) in:
  • Lesions > 0.8 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma thick 
  • Lesions of any thickness with ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers

Regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node dissection:

• Completion lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node dissection (CLND) (in those with positive SLNB), provided reduced regional lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node recurrence.
• However, there was no difference in survival in CLND versus observation.

Surgical metastasectomy Metastasectomy Surgery to remove one or more neoplasm metastases. Hepatocellular Carcinoma (HCC) and Liver Metastases:

• Can be done for isolated distant metastases
• Sometimes performed after good initial response to adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapy

Adjuvant Adjuvant Substances that augment, stimulate, activate, potentiate, or modulate the immune response at either the cellular or humoral level. The classical agents (freund’s adjuvant, bcg, corynebacterium parvum, et al.) contain bacterial antigens. Some are endogenous (e.g., histamine, interferon, transfer factor, tuftsin, interleukin-1). Their mode of action is either non-specific, resulting in increased immune responsiveness to a wide variety of antigens, or antigen-specific, i.e., affecting a restricted type of immune response to a narrow group of antigens. The therapeutic efficacy of many biological response modifiers is related to their antigen-specific immunoadjuvanticity. Vaccination therapies for advanced melanoma

• Usually not recommended for stage IIC and lower
• For stage III disease ( lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement) and stage IV (metastatic disease)
• Options:
  • Immunotherapy (combination of):
    • Nivolumab or pembrolizumab Pembrolizumab Squamous Cell Carcinoma (SCC) (anti–programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death antibody)
    • Ipilimumab (monoclonal antibody to cytotoxic Cytotoxic Parvovirus B19 T lymphocyte–associated antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination 4)
  • Targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy:
    • For BRAF V600E/K mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: combination vemurafenib Vemurafenib An indole sulfonamide compound and inhibitor of BRAF kinases that is used for the treatment of unresectable or metastatic melanoma. Targeted and Other Nontraditional Antineoplastic Therapy (BRAF kinase inhibitors) with cobimetinib Cobimetinib Targeted and Other Nontraditional Antineoplastic Therapy (MEK inhibitor)
    • Other option for BRAF V600E/K mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: dabrafenib DaBRAFenib Targeted and Other Nontraditional Antineoplastic Therapy + trametinib Trametinib Targeted and Other Nontraditional Antineoplastic Therapy, encorafenib + binimetinib
    • For KIT mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations: imatinib Imatinib A tyrosine kinase inhibitor and antineoplastic agent that inhibits the bcr-abl kinase created by chromosome rearrangements in chronic myeloid leukemia and acute lymphoblastic leukemia, as well as pdg-derived tyrosine kinases that are overexpressed in gastrointestinal stromal tumors. Targeted and Other Nontraditional Antineoplastic Therapy ( tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitor)
  • Cytotoxic Cytotoxic Parvovirus B19 therapy:
    • Not very effective and does not improve overall survival
    • Limited to patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship for whom other options have been exhausted
  • Radiotherapy: 
    • Mostly for palliation in locally advanced disease
    • Stereotactic radiosurgery has a role in brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis.

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

Negative prognostic factors: 

• Patient-related factors:
  • Advanced age
  • Men
• Lesion-related factors:
  • Advanced tumor Tumor Inflammation stage: tumor Tumor Inflammation thickness, ulceration Ulceration Corneal Abrasions, Erosion, and Ulcers, lymph Lymph The interstitial fluid that is in the lymphatic system. Secondary Lymphatic Organs node involvement, and presence of distant metastasis Metastasis The transfer of a neoplasm from one organ or part of the body to another remote from the primary site. Grading, Staging, and Metastasis
  • ↑ Mitotic rate
  • Nodular melanoma

5-year survival rate:

• Stage I: > 90%
• Stage II: 45%–77%
• Stage III: 27%–70%
• Stage IV: < 20%

Differential Diagnosis

• Atypical nevus Nevus Nevi (singular nevus), also known as “moles,” are benign neoplasms of the skin. Nevus is a non-specific medical term because it encompasses both congenital and acquired lesions, hyper- and hypopigmented lesions, and raised or flat lesions. Nevus/Nevi: a benign Benign Fibroadenoma melanocytic neoplasm that mimics melanoma in appearance, as it may be asymmetric and > 6 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma with color variegation. Thus, a biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is needed to exclude melanoma.
• Seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a “stuck-on” appearance. Seborrheic Keratosis: a benign Benign Fibroadenoma neoplasm consisting of immature keratinocytes Keratinocytes Epidermal cells which synthesize keratin and undergo characteristic changes as they move upward from the basal layers of the epidermis to the cornified (horny) layer of the skin. Successive stages of differentiation of the keratinocytes forming the epidermal layers are basal cell, spinous or prickle cell, and the granular cell. Skin: Structure and Functions occurring commonly in the elderly. A seborrheic keratosis Seborrheic keratosis Seborrheic keratosis (SK) is the most common benign epithelial cutaneous neoplasm. The condition consists of immature keratinocytes. Seborrheic keratosis is the most common benign skin tumor in middle-aged and elderly adults and presents as a sharply demarcated, exophytic, skin lesion that may be tan or black and has a “stuck-on” appearance. Seborrheic Keratosis usually presents as a sharply demarcated, round, exophytic Exophytic Retinoblastoma, dark skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesion.
• Dermatofibroma: a benign Benign Fibroadenoma proliferation of dermal fibroblasts Fibroblasts Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. Sarcoidosis that presents as a firm, indurated, mobile nodule Nodule Chalazion measuring about 0.5–1 cm in size. Furthermore, a dimple-like depression in the overlying skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions appears as a “buttonhole” sign upon lateral compression Compression Blunt Chest Trauma.
• Other skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions malignancies: squamous cell or basal cell Basal Cell Erythema Multiforme carcinomas usually present as raised erythematous, scaly, or ulcerated lesions. The malignancies can resemble amelanotic melanomas. Diagnosis is established by biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.